1. Field of the Invention
The present invention relates to bone metabolism improving agents that improve bone metabolism in the living body, and more specifically, to a bone metabolism improving agent that improves bone metabolism in a chronic renal failure patient who receives blood purification therapy such as hemodialysis, hemofiltration and hemodiafiltration.
Further, the present invention relates to methods for improving bone metabolism in a chronic renal failure patient who receives blood purification therapy such as hemodialysis, hemofiltration and hemodiafiltration, by administration of above bone metabolism improving agents; and more specifically, to a method for improving bone metabolism employing a dialysate and/or a substitution fluid that contain above bone metabolism improving agents.
Furthermore, the present invention relates to methods for blood purification including hemodialysis and hemodiafiltration in a chronic renal failure patient employing dialysates that contain above bone metabolism improving agents, and additionally to methods for blood purification including hemodiafiltration and hemofiltration in a chronic renal failure patient employing substitution fluids that contain above bone metabolism improving agents.
2. Discussion of the Background
Chronic renal failure patients who receive blood purification therapy, typically hemodialysis, suffer from lowered quality of life (QOL), hospitalization and high mortality rates induced by various complications. It is well known that causes of such complications include chronic inflammatory state, nutritional deficiencies, arteriosclerosis and anemia, and that interrelation among them deteriorates prognosis.
Because kidney plays a key role in conjunction with parathyroid glands, bone and intestinal tract in the intricate controlling system for maintaining calcium (Ca) and phosphorus (P) balances in the living body as well as keeping calcium ion concentrations of extracellular fluid within the physiological range, chronic renal failure with renal function disordered causes various abnormalities. One of such abnormalities is bone metabolism abnormality.
For example, chronic renal failure patients develop hypocalcemia induced by hyperphosphatemia due to lowered phosphorus excretion in the kidney. Renal hypofunction also causes phosphorus retention due to nephron reduction and low blood concentrations of 1α, 25-dihydroxyvitamin D, an activated vitamin D, induced by decreased hydroxylation of 25-hydroxyvitamin D at the 1-alpha position. Decreased blood concentrations of 1α, 25-dihydroxy-vitamin D cause calcium malabsorption at the small intestine as well as low serum calcium concentrations due to decreased bone resorption.
As a result of phosphorus retention, hypocalcemia and vitamin D activation disorder, secretion of parathyroid hormone (PTH) increases for compensation.
Disorder of renal function that plays key roles in controlling calcium and phosphorus concentrations in blood serum and vitamin D activation as mentioned above affects not only bone metabolism itself but also prognosis in the long term due to calcinosis in the blood vessel and whole body.
In renal failure patients, bone reactivity to PTH (bone turnover) is lowered because of phosphorus retention, activated vitamin D deficiency and PTH receptor disorder. According to bone histological findings, the blood PTH concentrations essential for maintaining normal bone turnover (intact PTH: i-PTH concentrations) in a dialysis patient are from 2.5 to 3 times higher than a healthy subject when the rate of osteogenesis is used as an indicator (Non-patent literature 1).
Generally the pathology that bone turnover is decreased with i-PTH concentrations falling below the normal range is called absolute hypoparathyroidism. In contrast, renal failure patients develop the pathology that normal bone turnover is not maintained notwithstanding normal i-PTH concentrations because of decreased bone reactivity to PTH—the pathology called relative hypoparathyroidism. Relative hypoparathyroidism has been considered to be a major cause of bone agenesis.
Thus, it has been assumed significant for improvement of QOL and prognosis of chronic renal failure patients receiving blood purification therapy such as hemodialysis, hemofiltration and hemodiafiltration to improve bone metabolism in adynamic bone disease by correcting blood ionized calcium concentrations. In line with the above, use of dialysis preparations whose calcium concentrations are set lower than general dialysis preparations has been recommended for treatment of adynamic bone disease.
However, use of such low-calcium dialysis preparations in blood purification therapy for a long time causes decreased bone mineral density in the body. As above, there has been developed no truly effective therapeutic agent up to the present.
Chronic renal failure patients also develop retention of water and uremic substances, electrolyte abnormality and metabolic acidosis induced by renal dysfunction. Especially, metabolic acidosis is known to accelerate hypermetabolism of proteins and amino acid (Non-patent literatures 2 and 3). Therefore, a major objective of hemodialysis is correction of blood acid-base balance.
In the early years of hemodialysis history, bicarbonate dialysis preparations that contain sodium hydrogencarbonate (sodium bicarbonate) as an alkalizer were used because sodium hydrogencarbonate is one of components of a main buffer system (i.e., carbonate buffer system) in the body. However, such bicarbonate dialysis preparations were not sufficient in stability because of carbonates precipitate due to existence of divalent ions such as calcium and magnesium.
Since then, acetate dialysis preparations that contain sodium acetate as an alkalizer were developed to supply hydrogencarbonate ions necessary for correction of acidosis.
After that, given sharp increase of dialysis patients suffering from acetate intolerance induced by use of acetate dialysis preparations, dialysis preparations that contain again sodium hydrogencarbonate as an alkalizer and a little amount of acetic acid (8-12 mEq/L) from necessity of formulation were developed. They are currently mainstream products in the market.
Recently, acetate-free dialysis preparations that contain no acetic acid and contain sodium hydrogencarbonate as the only alkalizer with citric acid-sodium citrate buffering system for a pH controller of dialysates have been suggested, though hydrogencarbonate was conventionally impossible for alkalizing agent.
The present inventors have newly found that above acetate-free dialysis preparations are effective in improvement of aforementioned bone metabolism abnormality developed in chronic renal failure patients receiving blood purification therapy for a long time and completed the invention.
Non-patent literature 1: Quarles L. D. et al., J. Clin. Endcrino. Metab. 75, 145, 1992.
Non-patent literature 2: Coles G. et al., Q. J. Med. 41, 25, 1972.
Non-patent literature 3: Mitch W. et al., Am. J. Kidney Dis. 38, 1337, 2001.